It has long been hypothesized that ventilatory support for respiratory failure may in itself contribute to lung damage. In support of this hypothesis, we have recently reported an increase in pulmonary microvascular permeability for peak airway pressures (Paw) above 42 cmH2O in isolated dog lungs. The studies will determine those pathologic and physiologic mechanisms which lower the threshold for microvascular injury by Paw. An isolated perfused lung preparation will be used in which we will measure the capillary filtration coefficient (Kf,c) protein reflection coefficient, isogravimetric pressure, critical capillary pressure for edema formation, pre/post-capillary resistance ratios, total vascular resistance, microvascular and large vessel resistance, vascular compliance and lung compliance. These measurements are sufficiently sensitive and reproducible that relatively modest differences in microvascular permeability and the distribution of vascular resistance can be reliably detected. We will determine the threshold Paw for microvascular injury and the effect of positive and expiratory pressure (PEEP) in: (1) open and closed chested rabbits to determine the effect of limitation of inflation volume; (2) dog lungs with small bronchi embolized with microbeads and saline to produce heterogeneous lung inflation; (3) adult lungs repeatedly lavaged to decrease intra-alveolar surface tension; (4) surfactant deficient premature lungs and newborn dog lungs; (5) adult dog lungs with a pre-existing graded microvascular injury induced by either oleic acid, HC1 aspiration, or endotoxin. In addition, the infiltration of leukocytes and tissue oxygen radical damage after Paw injury will be determined in intact dogs and the location of the capillary leak sites will be sought using methyl methacrylate casts of the microcirculation. These studies should reveal how lung overdistention, pre-existing capillary damage, regional collapse and regional shear stresses contribute to Paw injury, where the damage occurs and if PEEP limits microvascular damage by high Paw.